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1.
FASEB J ; 38(10): e23680, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38758186

RESUMEN

Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release, thereby playing pivotal roles in the intricate process of cellular fate modulation. Super elongation complex (SEC), a large assembly comprising diverse protein components, has garnered attention due to its emerging significance in orchestrating physiological and pathological cellular identity changes by regulating the transcription of crucial genes. Consequently, SEC emerges as a noteworthy functional complex capable of modulating cell fate alterations. Therefore, a comprehensive review is warranted to systematically summarize the core roles of SEC in different types of cell fate alterations. This review focuses on elucidating the current understanding of the structural and functional basis of SEC. Additionally, we discuss the intricate regulatory mechanisms governing SEC in various models of cell fate alteration, encompassing both physiological and pathological contexts. Furthermore, leveraging the existing knowledge of SEC, we propose some insightful directions for future research, aiming to enhance our mechanistic and functional comprehension of SEC within the diverse landscape of cell fate alterations.


Asunto(s)
Diferenciación Celular , Humanos , Animales , Diferenciación Celular/fisiología , Transcripción Genética
2.
Cell Mol Life Sci ; 81(1): 298, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38992327

RESUMEN

In spite of its essential role in culture media, the precise influence of lactate on early mouse embryonic development remains elusive. Previous studies have implicated lactate accumulation in medium affecting histone acetylation. Recent research has underscored lactate-derived histone lactylation as a novel epigenetic modification in diverse cellular processes and diseases. Our investigation demonstrated that the absence of sodium lactate in the medium resulted in a pronounced 2-cell arrest at the late G2 phase in embryos. RNA-seq analysis revealed that the absence of sodium lactate significantly impaired the maternal-to-zygotic transition (MZT), particularly in zygotic gene activation (ZGA). Investigations were conducted employing Cut&Tag assays targeting the well-studied histone acetylation and lactylation sites, H3K18la and H3K27ac, respectively. The findings revealed a noticeable reduction in H3K18la modification under lactate deficiency, and this alteration showed a significant correlation with changes in gene expression. In contrast, H3K27ac exhibited minimal correlation. These results suggest that lactate may preferentially influence early embryonic development through H3K18la rather than H3K27ac modifications.


Asunto(s)
Histonas , Ácido Láctico , Cigoto , Histonas/metabolismo , Histonas/genética , Animales , Acetilación , Cigoto/metabolismo , Ratones , Ácido Láctico/metabolismo , Desarrollo Embrionario/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Epigénesis Genética , Genoma , Procesamiento Proteico-Postraduccional
3.
Inorg Chem ; 63(13): 5872-5884, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38498970

RESUMEN

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.


Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Iridio , Especies Reactivas de Oxígeno/metabolismo , Ligandos , Rodaminas/farmacología , Línea Celular Tumoral , Fototerapia
4.
FASEB J ; 36(2): e22162, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35061304

RESUMEN

Apoptosis of alveolar epithelial cells is a critical initial link in the pathogenesis of acute lung injury (ALI), recent studies have revealed that Methyl-CpG binding domain protein 2 (MBD2) was involved in the execution of apoptosis, yet its role in ALI remained unclear. In the present study, we aim to explore the role and mechanism of MBD2 in the pathogenesis of ALI. We have found that MBD2 expression, in parallel to apoptosis, increased in alveolar epithelial cells of mice treated with LPS, knockout of MBD2 reduced apoptosis and protected mice from LPS-induced ALI. In MLE-12 cells, a cell line of murine alveolar epithelial cells, LPS induced MBD2 expression and apoptosis in a dose- and time-dependent manner. Knockdown of MBD2 with shRNA alleviated, while overexpression of MBD2 increased LPS-induced apoptosis. Mechanistically, intracellular zinc level decreased when MLE-12 cells were treated with LPS. MBD2 knockdown restored intracellular zinc level after LPS treatment, and MBD2 overexpression further aggravated LPS-induced intracellular zinc loss. Metal transcription factor 1 (MTF1) is a critical transcription factor in charge of intracellular zinc efflux. LPS treatment induced MTF1 expression both in vivo and in vitro. Inhibition of MTF1 reduced LPS-induced apoptosis in MLE-12 cells. MBD2 could bind to the promoter region of MTF1 and promote MTF1 expression. Collectively, these data indicated that loss of MBD2-ameliorated LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis by upregulating MTF1.


Asunto(s)
Lesión Pulmonar Aguda/genética , Células Epiteliales Alveolares/metabolismo , Apoptosis/genética , Proteínas de Unión al ADN/genética , Homeostasis/genética , Zinc/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Homeostasis/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Ratones , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
5.
Theor Appl Genet ; 135(4): 1413-1427, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35187586

RESUMEN

KEY MESSAGE: We developed the ZDX1 high-throughput functional soybean array for high accuracy evaluation and selection of both parents and progeny, which can greatly accelerate soybean breeding. Microarray technology facilitates rapid, accurate, and economical genotyping. Here, using resequencing data from 2214 representative soybean accessions, we developed the high-throughput functional array ZDX1, containing 158,959 SNPs, covering 90.92% of soybean genes and sites related to important traits. By application of the array, a total of 817 accessions were genotyped, including three subpopulations of candidate parental lines, parental lines and their progeny from practical breeding. The fixed SNPs were identified in progeny, indicating artificial selection during the breeding process. By identifying functional sites of target traits, novel soybean cyst nematode-resistant progeny and maturity-related novel sources were identified by allele combinations, demonstrating that functional sites provide an efficient method for the rapid screening of desirable traits or gene sources. Notably, we found that the breeding index (BI) was a good indicator for progeny selection. Superior progeny were derived from the combination of distantly related parents, with at least one parent having a higher BI. Furthermore, new combinations based on good performance were proposed for further breeding after excluding redundant and closely related parents. Genomic best linear unbiased prediction (GBLUP) analysis was the best analysis method and achieved the highest accuracy in predicting four traits when comparing SNPs in genic regions rather than whole genomic or intergenic SNPs. The prediction accuracy was improved by 32.1% by using progeny to expand the training population. Collectively, a versatile assay demonstrated that the functional ZDX1 array provided efficient information for the design and optimization of a breeding pipeline for accelerated soybean breeding.


Asunto(s)
Glycine max , Fitomejoramiento , Alelos , Estudio de Asociación del Genoma Completo , Genotipo , Polimorfismo de Nucleótido Simple , Glycine max/genética
6.
Mol Psychiatry ; 26(4): 1152-1161, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-31462767

RESUMEN

Different substance dependences have common effects on reward pathway and molecular adaptations, however little is known regarding their shared genetic factors. We aimed to identify the risk genetic variants that are shared for substance dependence (SD). First, promising genome-wide significant loci were identified from 3296 patients (521 alcoholic/1026 heroin/1749 methamphetamine) vs 2859 healthy controls and independently replicated using 1954 patients vs 1904 controls. Second, the functional effects of promising variants on gene expression, addiction characteristics, brain structure (gray and white matter), and addiction behaviors in addiction animal models (chronic administration and self-administration) were assessed. In addition, we assessed the genetic correlation among the three SDs using LD score regression. We identified and replicated three novel loci that were associated with the common risk of heroin, methamphetamine addiction, and alcoholism: ANKS1B rs2133896 (Pmeta = 3.60 × 10-9), AGBL4 rs147247472 (Pmeta = 3.40 × 10-12), and CTNNA2 rs10196867 (Pmeta = 4.73 × 10-9). Rs2133896 in ANKS1B was associated with ANKS1B gene expression and had effects on gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus in heroin dependence. Overexpression of anks1b gene in the ventral tegmental area decreased addiction vulnerability for heroin and methamphetamine in self-administration rat models. Our findings could shed light on the root cause for substance dependence and will be helpful for the development of cost-effective prevention strategies for general addiction disorders.


Asunto(s)
Alcoholismo , Trastornos Relacionados con Anfetaminas , Dependencia de Heroína , Metanfetamina , Alcoholismo/genética , Trastornos Relacionados con Anfetaminas/genética , Animales , Heroína , Dependencia de Heroína/genética , Humanos , Ratas
7.
J Integr Plant Biol ; 64(3): 632-648, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34914170

RESUMEN

Innovations in genomics have enabled the development of low-cost, high-resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole-genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high-confidence genes. Identity-by-state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome-wide association mapping in combination with reported quantitative trait loci enabled fine-mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research.


Asunto(s)
Glycine max , Polimorfismo de Nucleótido Simple , Genoma de Planta/genética , Estudio de Asociación del Genoma Completo , Genómica , Genotipo , Fitomejoramiento , Polimorfismo de Nucleótido Simple/genética , Glycine max/genética
8.
Pharm Biol ; 60(1): 2286-2294, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36433644

RESUMEN

CONTEXT: Ferulic acid (FA) has antioxidative and anti-inflammatory effects, and is a promising drug to treat sepsis. OBJECTIVE: To study the therapeutic effect of FA in sepsis-induced acute lung injury (ALI) and its underlying mechanisms. MATERIALS AND METHODS: The caecal ligation and puncture (CLP) manoeuvre was applied to establish a murine model of sepsis-induced ALI, and female BALB/c mice (6 mice per group) were subjected to 100 mg/kg FA or 0.8 mg/kg ferrostatin-1 (Fer-1, ferroptosis inhibitor) treatment to clarify the role of FA in preserving alveolar epithelial barrier function and inhibiting ferroptosis. Lipopolysaccharide (LPS; 500 ng/mL)-induced cell models were prepared and subjected to FA (0.1 µM), sh-Nrf2, and Fe (Fe-citrate, ferroptosis inducer; 5 M) treatment to study the in vitro effect of FA on LPS-induced alveolar epithelial cell injury and the role of the Nrf2/HO-1 pathway. RESULTS: We found that FA decreased the lung injury score (48% reduction), lung wet/dry weight ratio (33% reduction), and myeloperoxidase activity (58% reduction) in sepsis-induced ALI. Moreover, FA inhibited ferroptosis of alveolar epithelial cells and improved alveolar epithelial barrier dysfunction. The protective role of FA against alveolar epithelial barrier dysfunction could be reversed by the ferroptosis inducer Fe-citrate, suggesting that FA alleviates alveolar epithelial barrier dysfunction by inhibiting ferroptosis. Mechanistically, we found that FA inhibited ferroptosis of alveolar epithelial cells by activating the Nrf2/HO-1 pathway. CONCLUSION: Collectively, our data highlighted the alleviatory role of ferulic acid in sepsis-induced ALI by activating the Nrf2/HO-1 pathway and inhibiting ferroptosis, offering a new basis for sepsis treatment.


Asunto(s)
Lesión Pulmonar Aguda , Ferroptosis , Sepsis , Femenino , Ratones , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Lipopolisacáridos/farmacología , Transducción de Señal , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/prevención & control , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Antioxidantes/uso terapéutico , Ratones Endogámicos BALB C , Citratos/farmacología
9.
Appl Opt ; 60(5): 1250-1259, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33690567

RESUMEN

Laser scanning projection can project outlines of assembled components onto a work surface accurately, which can improve assembly efficiency, and is widely applied in industry manufacturing. In order to achieve accurate calibration and projection, a mathematical model of the calibration process is developed, and the dual-diameter fitting method is proposed to extract the central positions of retroreflective targets. Then, a particle swarm optimization (PSO) algorithm is introduced to solve the coordinate transformation matrix between the world frame and the projector frame, and the optimal parameters of the PSO algorithm are obtained to improve the convergence probability of the transformation matrix solutions. The maximum error of the retroreflective targets' central positions between the calculated and theoretical positions is 1.82×10-6mm through the simulation experiment. Furthermore, a novel laser scanning projection setup and a control system based on LabVIEW are developed. Experiments are actually carried out by scanning six retroreflective targets on a standard workpiece, and the transformation matrix is solved correspondingly. The results indicate that the maximum beam steering angle error between the theoretical and actual values calculated by the abovementioned transformation matrix is 5.215668×10-9 degrees. Finally, the projection accuracy is verified by a standard workpiece with accurate patterns. The experiment results prove that the position error of the developed laser scanning projection system is better than 0.5 mm.

10.
Aging Clin Exp Res ; 32(5): 789-796, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31352587

RESUMEN

BACKGROUND AND AIMS: This study aimed to investigate the association between cumulative C-reactive protein (cumCPR) and arterial stiffness. METHODS: The cross-sectional study included 15,432 participants from the Kailuan Cohort. The participants were divided into four groups according to cumCRP quartiles. The average brachial-ankle pulse wave velocity (baPWV) and detective rate of increased arterial stiffness were compared between exposure groups. Statistical analysis was performed with multiple logistic regression analysis to estimate the association between cumCRP and arterial stiffness by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). The several sensitivity analyses were performed to test the robustness of our findings. RESULTS: The average baPWV increased from 1425.70 cm/s of Q1 group to 1626.48 cm/s of Q4 group. And the detective rate of arterial stiffness increased from 44.7 to 70.1% (P < 0.001). Multiple logistic regression analysis showed that after adjusting the confounding factors, compared to the Q1 group, the Q4 group had 42% (adjusted OR 1.42; 95% CI 1.24-1.63) higher arterial stiffness risk. In addition, 10% (adjusted OR 1.10; 95% CI 1.02-1.18) arterial stiffness risk was increased per 1 standard deviation (SD) of cumCRP after a fully adjusted regression model. CONCLUSION: Higher cumCRP exposure is associated with increased arterial stiffness.


Asunto(s)
Proteína C-Reactiva/análisis , Rigidez Vascular , Adulto , Anciano , Índice Tobillo Braquial , Articulación del Tobillo , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Análisis de la Onda del Pulso , Factores de Riesgo
11.
Biochem Biophys Res Commun ; 497(2): 564-570, 2018 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-29448096

RESUMEN

Chronic obstructive pulmonary disease (COPD), is characterized by inflammation of airways accompanied by a progressive destruction of lung parenchyma. This process is initiated in most cases by cigarette smoking. In this study we investigated the role of AMP activated protein kinase (AMPK) in cigarette smoke extract (CSE)-induced airway epithelial cell apoptosis as a consequence of endoplasmic reticulum stress (ER stress). Exposure of human bronchial epithelial cells (HBEpC) to CSE resulted in apoptosis as detected using Annexin V-PI flow cytometry. However, co-treatment with N1-(ß-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly increased cell protection against ER stress-induced apoptosis by upregulating the 150 kDa oxygen-regulated protein (ORP150), which functions as an ER-associated chaperone, with concomitant elevation of FOXO1, a critical transcription factor regulating ORP150 expression. Lentiviral silencing of AMPK or FOXO1 using short hairpin (sh) RNA resulted in a significant decrease of ORP150 and an elevation of CCAAT/enhancer-binding protein-homologous protein (CHOP) resulting in ER stress and apoptosis of HBEpC. Together, our results strongly suggest that AMPK can activate ORP150 through FOXO1 pathway and confer protection against ER stress-induced apoptosis of airway epithelial cells following exposure to CSE. Thus, AMPK may serve as a likely therapeutic target for clinical and sub-clinical interventions in COPD.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis , Bronquios/citología , Estrés del Retículo Endoplásmico , Proteína Forkhead Box O1/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Bronquios/metabolismo , Línea Celular , Fumar Cigarrillos/efectos adversos , Fumar Cigarrillos/metabolismo , Humanos , Mapas de Interacción de Proteínas , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Humo/efectos adversos , Humo/análisis , Nicotiana/química
12.
Guang Pu Xue Yu Guang Pu Fen Xi ; 37(2): 467-71, 2017 Feb.
Artículo en Zh | MEDLINE | ID: mdl-30265484

RESUMEN

Oilseed rape(Brassica napus L. ) is a principal source of edible oil for human consumption and it feeds livestock as a by product with high energy and protein. However, oilseed plants often suffer from the invasion of various diseases, which could affect the yield and quality of the rapeseeds. Rape sclerotinia rot caused by the fungus sclerotinia sclerotiorum (Lib. ) de Bary may severely affect the growth of oilseed rape. Therefore, searching non-invasive detection methods of detection plant disease at early stage is crucial for monitoring growing conditions of crops. Confocal Raman spectroscopy in the region of 500~2 000 cm(-1) coupled with chemometrics methods were employed to discriminate the rape sclerotinia disease at early stage on the oilseed rape leaves. A total of 60 samples(30 healthy plant leaves and 30 infected leaves) were used to acquire the Raman spectra and wavelet transform was applied to remove the fluorescence background. Regression coefficients of the partial least squares-discriminant analysis(PLS-DA) were used to select the 8 characteristic peaks based on the whole Raman spectra. 983,1 001, 1 205, 1 521, 1 527, 1 658, 1 670 and 1 758 cm(-1) were employed to establish PLS-DA discriminate models and recognition accuracy was 100%. The results showed Raman spectra combined with chemometrics method is promising for detecting rape sclerotinia infection in the oilseed rape leaves at early stage. This study provided a theoretical reference for researching the interaction between the fungus and plants and early detecting of disease infection.


Asunto(s)
Brassica , Espectrometría Raman , Ascomicetos , Análisis de los Mínimos Cuadrados , Enfermedades de las Plantas , Hojas de la Planta
13.
Bioorg Med Chem Lett ; 24(6): 1479-83, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24565904

RESUMEN

A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure-activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC50=9.20µM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC50=7.07µM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well.


Asunto(s)
Benzoxazinas/química , Piperazinas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Benzoxazinas/síntesis química , Benzoxazinas/metabolismo , Sitios de Unión , Dominio Catalítico , Simulación del Acoplamiento Molecular , Piperazinas/química , Piperazinas/metabolismo , Inhibidores de Agregación Plaquetaria/química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Relación Estructura-Actividad
14.
Cell Rep ; 43(3): 113840, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38386558

RESUMEN

Recent studies have elucidated Nr5a2's role in activating zygotic genes during early mouse embryonic development. Subsequent research, however, reveals that Nr5a2 is not critical for zygotic genome activation but is vital for the gene program between the 4- and 8-cell stages. A significant gap exists in experimental evidence regarding its function during the first lineage differentiation's pivotal period. In this study, we observed that approximately 20% of embryos developed to the blastocyst stage following Nr5a2 ablation. However, these blastocysts lacked inner cell mass (ICM), highlighting Nr5a2's importance in first lineage differentiation. Mechanistically, using RNA sequencing and CUT&Tag, we found that Nr5a2 transcriptionally regulates ICM-specific genes, such as Oct4, to establish the pluripotent network. Interference with or overexpression of Nr5a2 in single blastomeres of 2-cell embryos can alter the fate of daughter cells. Our results indicate that Nr5a2 works as a doorkeeper to ensure ICM formation in mouse blastocyst.


Asunto(s)
Blastocisto , Desarrollo Embrionario , Embarazo , Femenino , Animales , Ratones , Desarrollo Embrionario/genética , Diferenciación Celular/genética , Blastómeros , Cigoto , Regulación del Desarrollo de la Expresión Génica , Receptores Citoplasmáticos y Nucleares/genética
15.
J Mater Chem B ; 12(15): 3710-3718, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38529668

RESUMEN

Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(III) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.


Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes , Silanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fotoquimioterapia/métodos , Iridio/farmacología , Iridio/química , Rodaminas , Línea Celular Tumoral , Rayos Infrarrojos
16.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166885, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37714499

RESUMEN

Perioperative hyperoxia therapy is of great significance to save the lives of patients, but little is known about the possible mechanisms that induce hyperoxia-induced acute lung injury (HALI) and the measures for clinical prevention and treatment. In this experiment, the models were established with a feeding chamber with automatic regulation of oxygen concentration. The results showed that with the increase in inhaled oxygen concentration and the prolongation of exposure time, the severity of lung injury also increases significantly, reaching the diagnostic indication of HALI after 48 h of inhaling 95 % oxygen concentration. Subsequently, according to the dynamic changes of apoptosis in lung specimens, and the expression changes in Sig-1R-regulated ER stress pathway proteins (Sig-1R, GRP78, p-PERK, ATF6, IRE1, Caspase-12, ATF4, CHOP, Caspase-3 and p-JNK), it was confirmed that the Sig-1R-regulated ER stress signaling pathway was involved in the occurrence of HALI. To explore the preventive and therapeutic effects of routine clinical medication on HALI during the perioperative period, our research group selected dexmedetomidine (Dex) with lung protection. The experimental results revealed that Dex partially reversed the changes in the expression levels of Sig-1R-regulated ER stress pathway proteins. These results preliminarily confirmed that Dex may inhibit apoptosis induced by high oxygen concentration through the Sig-1R-regulated ER stress signaling pathway, thus playing a protective role in HALI.


Asunto(s)
Lesión Pulmonar Aguda , Dexmedetomidina , Hiperoxia , Humanos , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Hiperoxia/complicaciones , Estrés del Retículo Endoplásmico , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/prevención & control , Oxígeno , Receptor Sigma-1
17.
Digit Health ; 9: 20552076231171482, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37179744

RESUMEN

Background: Although the machine learning model developed on electronic health records has become a promising method for early predicting hospital mortality, few studies focus on the approaches for handling missing data in electronic health records and evaluate model robustness to data missingness. This study proposes an attention architecture that shows excellent predictive performance and is robust to data missingness. Methods: Two public intensive care unit databases were used for model training and external validation, respectively. Three neural networks (masked attention model, attention model with imputation, attention model with missing indicator) based on the attention architecture were developed, using masked attention mechanism, multiple imputation, and missing indicator to handle missing data, respectively. Model interpretability was analyzed by attention allocations. Extreme gradient boosting, logistic regression with multiple imputation and missing indicator (logistic regression with imputation, logistic regression with missing indicator) were used as baseline models. Model discrimination and calibration were evaluated by area under the receiver operating characteristic curve, area under precision-recall curve, and calibration curve. In addition, model robustness to data missingness in both model training and validation was evaluated by three analyses. Results: In total, 65,623 and 150,753 intensive care unit stays were respectively included in the training set and the test set, with mortality of 10.1% and 8.5%, and overall missing rate of 10.3% and 19.7%. attention model with missing indicator had the highest area under the receiver operating characteristic curve (0.869; 95% CI: 0.865 to 0.873) in external validation; attention model with imputation had the highest area under precision-recall curve (0.497; 95% CI: 0.480-0.513). Masked attention model and attention model with imputation showed better calibration than other models. The three neural networks showed different patterns of attention allocation. In terms of robustness to data missingness, masked attention model and attention model with missing indicator are more robust to missing data in model training; while attention model with imputation is more robust to missing data in model validation. Conclusions: The attention architecture has the potential to become an excellent model architecture for clinical prediction task with data missingness.

18.
Front Neurosci ; 17: 1137559, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37065913

RESUMEN

Background: It remains unclear whether very preterm (VP) infants have the same level of brain structure and function as full-term (FT) infants. In addition, the relationship between potential differences in brain white matter microstructure and network connectivity and specific perinatal factors has not been well characterized. Objective: This study aimed to investigate the existence of potential differences in brain white matter microstructure and network connectivity between VP and FT infants at term-equivalent age (TEA) and examine the potential association of these differences with perinatal factors. Methods: A total of 83 infants were prospectively selected for this study: 43 VP infants (gestational age, or GA: 27-32 weeks) and 40 FT infants (GA: 37-44 weeks). All infants at TEA underwent both conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Significant differences in white matter fractional anisotropy (FA) and mean diffusivity (MD) images between the VP and FT groups were observed using tract-based spatial statistics (TBSS). The fibers were tracked between each pair of regions in the individual space, using the automated anatomical labeling (AAL) atlas. Then, a structural brain network was constructed, where the connection between each pair of nodes was defined by the number of fibers. Network-based statistics (NBS) were used to examine differences in brain network connectivity between the VP and FT groups. Additionally, multivariate linear regression was conducted to investigate potential correlations between fiber bundle numbers and network metrics (global efficiency, local efficiency, and small-worldness) and perinatal factors. Results: Significant differences in FA were observed between the VP and FT groups in several regions. These differences were found to be significantly associated with perinatal factors such as bronchopulmonary dysplasia (BPD), activity, pulse, grimace, appearance, respiratory (APGAR) score, gestational hypertension, and infection. Significant differences in network connectivity were observed between the VP and FT groups. Linear regression results showed significant correlations between maternal years of education, weight, the APGAR score, GA at birth, and network metrics in the VP group. Conclusions: The findings of this study shed light on the influence of perinatal factors on brain development in VP infants. These results may serve as a basis for clinical intervention and treatment to improve the outcome of preterm infants.

19.
Urology ; 177: 134-141, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37088316

RESUMEN

OBJECTIVE: To investigate the application of multiparametric magnetic resonance imaging (mp-MRI) for comprehensive evaluation of the correlation between the characteristics of the transitional zone and the International Prostate Symptom Score (IPSS) in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We retrospectively recruited 210 patients with biopsy-proven BPH who underwent preoperative mp-MRI and were assigned an IPSS. The evaluation indicators included prostate volumetric parameters (total prostate volume [TPV], transition zone volume [TZV], and transition zone index [TZI, TZI=TZV/TPV]), prostate morphological parameters (intravesical prostatic protrusion, and presumed circle area ratio) and prostate compositional parameters (apparent diffusion coefficient [ADC], and mean signal intensity of T2WI [mean-SI-T2WI]). The Pearson (r) correlation coefficient, one-way analysis of variance, and multiple linear regression analysis were used to build a regression model for evaluating the correlation between MRI-derived parameters and IPSS, IPSS-storage symptom, IPSS-voiding symptom. RESULTS: Significant correlations were found between IPSS, IPSS-storage symptom, IPSS-voiding symptom, and prostate MRI-derived parameters, including TPV (r = 0.350; r = 0.466; r = 0.225, P < .001), TZV (r = 0.374; r = 0.492; r = 0.243, P < .001), TZI (r = 0.383; r = 0.313; r = 0.354, P < .001), presumed circle area ratio (r = 0.481; r = 0.356; r = 0.469, P < .001), ADC(r = -0.198; r = -0.053; r = -0.239, P < .05) and mean-SI-T2WI (r = -0.626; r = -0.310; r = -0.687, P < .001), respectively. Based on multiple linear regression analysis, the impact of mean-SI-T2WI and TZI on total IPSS were statistically significant (P < .05), and the regression equation established with the analysis (IPSS= 39.224 + 8.469 ×TZI+ (-0.09)× (mean-SI-T2WI)) was statistically significant (F=104.995, P < .001). CONCLUSION: Mp-MRI could be used to evaluate the volume and morphology of BPH. In particular, mean-SI-T2WI and ADC could be used to describe the internal composition of the prostate. The imaging parameters were effective for evaluating BPH.


Asunto(s)
Imágenes de Resonancia Magnética Multiparamétrica , Hiperplasia Prostática , Masculino , Humanos , Próstata/diagnóstico por imagen , Próstata/patología , Hiperplasia Prostática/cirugía , Estudios Retrospectivos , Imagen por Resonancia Magnética
20.
Sci Data ; 9(1): 244, 2022 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-35624183

RESUMEN

High-speed train operation data are reliable and rich resources in data-driven research. However, the data released by railway companies are poorly organized and not comprehensive enough to be applied directly and effectively. A public high-speed railway network dataset suitable for research is still lacking. To support the research in large-scale complex network, complex dynamic system and intelligent transportation, we develop a high-speed railway network dataset, containing the train operation data in different directions from October 8, 2019 to January 27, 2020, the train delay data of the railway stations, the junction stations data, and the mileage data of adjacent stations. In the dataset, weather, temperature, wind power and major holidays are considered as factors affecting train operation. Potential research values of the dataset include but are not limited to complex dynamic system pattern mining, community detection and discovery, and train delay analysis. Besides, the dataset can be used to solve various railway operation and management problems, such as passenger service network improvement, train real-time dispatching and intelligent driving assistance.

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